12alpha-halo steroids of the pregnane series



United States Patent Office Patented June 13, 1961 2,988,555 Hot-HALOSTEROIDS OF THE PREGNANE SERIES Josef Fried and Josef E. Herz, NewBrunswick, N.J., as-

signors to Olin Mathieson Chemical Corporation, New 5 This applicationis a continuation-in-part of our parent application, Serial No. 519,682,filed July 1, 1955, and a division of our parent application, Serial No.668,596, filed June 28, 1957.

This invention relates to the synthesis of valuable steroids; and hasfor its object the provision of (I) an advantageous process of preparingsteroids of the pregnane (including the allopregnane, pregnene andpregnadiene) series having a Hot-halogen substituent and an ll-keto orllfl-hydroxy substituent, and of (H) certain steroids useful themselvesas physiologically active steroids or in the preparation ofphysiologically active steroid derivatives.

The process of this invention essentially comprises: (a) converting an11 8,12/S'-epoxy steroid of the pregnane (including the allopregnane,pregnene, and pregnadiene) series into the corresponding12a-halo-11fl-hydroxy de- CHzY rivative thereof; (b) converting said12a-ha1o-11fi-hydroxy derivative to the corresponding 4/3-bromo (or2,4-dibromo) derivative, and thence by dehydrobromination to thecorresponding A -pregnene (or a mixture of the corresponding A-pregnadiene and A -pregnadiene) derivative (if the initialIIfiJZB-steroid contains the requisite 4,5- and/or l,2;4,5- and4,5;6,7-unsaturation, step b can, of course, be eliminated); and (c)optionally oxidizing the llp-hydroxy steroid, thus formed, to thecorresponding ll-keto derivative.

The compounds of this invention comprise: (A) the intermediatel2a-halo-ll 3-hydroxy steroids of pregnane (including the allopregnane)series, wherein the halo radical is chlorine or fluorine (i.e. a halogenof atomic weight greater than 18 and less than 36); (B) the intermediate12u-halo-4fl-bromo-1lfl-hydroxy steroids of the pregnane series; (C) theintermediate 12m-halo-2,4-dibromo-l15- hydroxy steroids of the pregnane(including the allopregnane) series; and (D) the physiologically active12u-halo- 11 fi-hydroxy (or 11-keto)-A -steroids of the pregnene(including the A and A -pregnadiene) series.

For a clearer understanding of the foregoing general and followingdetailed description of the processes of this invention, reference ismade to the following schematic and wherein the 1,2;4,5; and6,7-positions are double-bonded or saturated, and wherein individually Ris hydrogen, R is hydroxy, or together R and R is oxo (keto) or a groupconvertible thereto by hydrolysis (e.g. ketal), R and R as keto beingpreferred, X is halogen [preferably a halogen of atomic weight greaterthan 18 and less than 36 (i.e. chlorine or fluorine)], Y is hydrogen,hydroxy, or acyloxy, and Z is hydrogen or a-hydroxy.

Compounds suitable as initial reactants in the process of this inventionare disclosed in said application, Serial No. 519,682, and includepreferably 11b,12b-epoxy-pregnane-3,20-dione and 115,125epoxypregnane-2l-ol-3,20- dione and esters thereof [particularlycarboxylic acid esters such as hydrocarbon carboxylic acid esters havingless than ten carbon atoms in the acid moiety, as exemplified by thelower alkanoic acid esters (eg the acetate, propionate, butyrate andenanthate), the monocyclic hydro carbon aromatic carboxylic acid esters(e.g. the benzoate), the lower cycloalkanecarboxylic acid esters, themonocyclic hydrocarbon aralkanoic acid esters (e.g. the phenacetate) thelower alkenoic acid esters, and the lower cycloalkenecarboxylic acidesters], although other starting materials may also be used, such as:115,12fl-epoxyprogesterone; 11B,12fi-epoxy-A -pregnene-2l-ol-3,20-dioneand esters thereof; 1113,12fl epoxy A pregnene-17u-ol- 3,20 dione;llfi,l2fl-epoxy-A -pregnene-17a,21-diol-3,20- dione and esters thereof;11B,12;3-epoxypregnane-17a-ol- 3 ,ZO-dione; 11/3,l2fi-epoxypregnane-17a,2l-diol-3,20-dione and esters thereof;11B,12B-epoxy-A -pregnadiene-3,20- dione; l 1B,1 2;3-epoxy-A-pregnadiene-17a-ol-3,2O-dione; 1lfi,12,8-epoxy-A-pregnadiene-Zl-ol-3,2O-dione and esters thereof; 1 lfl,l2p-epoxy-A-pregnadiene-17u,21-diol- 3,20-dione and esters thereof;115,12/3-epoxy-A -pregnadiene-3,20-dione; ll5,1ZB-epoxy-A-pregnadiene-17a-o1- 3 ,20-dione; 11B,l213-epoxy-A-pregnadiene-2l-ol-3,20-dione and esters thereof; and 1l 3,12B-epoxy-A-pregnadione-17mll-diol-3,20-dione and esters thereof.

These 115,12fi-epoxy steroids are reacted with a hydrogen halide (e.g.hydrobromic, hydroiodic, and preferably hydrofluoric and hydrochloricacid) in a suitable organic solvent, such as a halogenated alkane (e.g.chloroform), an alcohol (e.g. methanol), or an ether (e.g. dioxane).

By this reaction, Compounds A are formed, wherein the 12a-halosubstituent corresponds to the halide of the hydrohalic acid of thereaction.

If the 115,12fi-epoxy reactant is saturated in the 1,2; 4,5; and 6,7positions (such reactants being preferred), the resultant inactiveCompounds A can be converted to physiologically active steroids byintroducing a doublebond in the 4,5-position. This may be done by: (1)reacting Compound A, wherein the steroid nucleus is saturated and of thepregnane configuration, with approximately one mole of bromine per moleof steroid, thereby forming Compounds B containing a 4fi-bromosubstituent, and dehydrobrominating as by treatment with an alkali metalhalide (such as an alkali metal chloride, as exemplified by lithiumchloride) or with a hydrazine derivative (e.g. dinitrophenylhydrazine orsemicarbazide) to form the corresponding hydrazone or semicarbazone,followed by decomposition of the latter with a keto acid (e.g. pyruvicacid) to yield a A -pregnene, Compounds C, which correspond to startingCompounds A except that the 4,5-position is double-bonded; or (2)reacting Compounds A, wherein the steroid nucleus is saturated and maybe either of the pregnane or allopregnane configuration, with at leasttwo moles of bromine per mole of steroid, thereby forming Compounds Dcontaining a 2,4-dibromo substituent (211,40; if Compounds A areallopregnanes and 213,413 if Compounds A are pregnanes), anddehydrobrominating by treatment with an organic base such as pyridine orcollidine, to prepare a mixture (which is separable by chromatography)of a A -pregnadiene, Compounds E, and a A -pregnadiene, Compounds E'.These derivatives correspond to starting Compounds A except that the4,5-position and one of the positions 1,2 or 6,7 is double-bonded.

Compounds A, C, E, and E' can be oxidized, if desired, to thecorresponding ll-keto derivatives, Compounds F, by treatment with anoxidizing agent such as a hexavalent chromium compound (e.g. chromicacid).

The new 12a-halo-11B-hydroxy (or 11-keto)-A -pregnene (including thepregnadiene) steroids of this invention (Compounds C, E, E, and F) andparticularly those of the general formula CHzY wherein the 1,2- and6,7-positions are saturated or doublebonded; R, R, X, Y and Z are ashereinbefore defined; and individually R is hydrogen, R' is hydroxy, andtogether R" and R' represents keto, are physiologically active steroidswhich possess glucocorticoid as well as mineralocorticoid activity.Thus, the new steroids of this invention can be administered instead of,and in the same manner as, cortisone or hyd-rocortisone in the treatmentof rheumatoid arthritis and dermatomyositis, or in the same manner asdesoxycorticosterone in the treatment of Addisons disease or adrenalinsufficiencies. The dosage for such administration is, of course,dependent on the relative activity of the compound. Thus, where thesteroid derivative has approximately the same activity of cortisone, thedosage of the former to be employed should be approximately equal to theemployed dosage of the latter. The IZoz-bIOIHO-ll-kGtO- steroids of thisinvention are of further use as intermediates in the preparation of thecorresponding 12-debromo derivatives, to which they are converted bytreatment either with zinc in acetic acid or chromous chloride.

For the purpose of illustrating the preferred process of this invention,reference is made to the following schematic analysis employing11p,12B-epoxy-pregnane-3,20- dione as the starting material:

The following examples are illustrative of the invention (alltemperatures being in centigrade):

EXAMPLE 1 IZa-chloropregnane-I 1 p-ol-3,20-dione (I) To a solution of 63mg. of 115,12fi-epoxypregnane- 3,20-dione in 10 ml. of pure dioxane isadded 2.5 m1. of 2.5 N aqueous hydrochloric acid. The mixture is stirredat room temperature for 1 hour after which 30 ml. of chloroform isadded. Separation of the layers followed by Washing of thechloroform-dioxane phase with dilute sodium bicarbonate solution andwith water and subsequent drying over sodium sulfate furnishes afterevaporation of the solvent in vacuo about 65 mg. of essentially purel2a-chloropregnane-l lfl-ol-3,20-dione (I): M.P. about 241-244 (dec.).The analytically pure substance has the following properties: M.P. about246-248" (dec.); [cc] (c, 0.31 in chloroform) N'uiol 2.96,. (OH), 5.83,.(3-keto), 5.95,. (20-keto) Analysis.-Calcd. for C H O 'Cl (366.92): C,68.74; H, 8.52;Cl, 9.66. Found: C, 69.16; H, 8.50; CI. 9.36.

EXAMPLE 2 12a-fluoropregnane-llfl-ol-3,20-dione (II To a solution of 250mg. of 115,12/3-ep0xypregnane- 3,20-dione in 24 ml. of chloroform and1.25 ml. of ethanol is added at 0 with stirring hydrogen fluoride untiltwo layers become definitely discernible. The mixture is stirred for atotal of 1 hour and 25 minutes at 0 and is then neutralized by theaddition of an aqueous suspension of sodium bicarbonate. The chloroformlayer is washed with water, dried over sodium sulfate and evaporated todryness in vacuo. The residue on crystallization from acetone-hexanefurnishes about 94 mg. of 9a-fiuoropregnane-12B-ol-3,20-dione having thefollowing properties: M.P. about 187-189; [a] 4 (c, 0.96 in chloroform);

$32 2.93 (OH), 5.86,. (3-keto), 5.92,. (20-keto) A353; No specificabsorption.

Analysis.-Calcd. for C H O F (350.42): C, 71.98; H, 8.90; F, 5.43.Found: C, 72.01; H, 8.98; 'F, 5.50.

The combined mother liquors from the above crystallization are dried invacuo and the resulting residue dissolved in 4 ml. of benzene and 4 ml.of hexane for chromatography on 3.46 g. of acid-washed alumina. Elutionwith equal volumes of benzene-hexane elutes amorphous impurities, whichare followed by crystalline fractions when the eluant is changed tobenzene (400 ml.) and 5% chloroform in benzene (450 ml.).Recrystallization of these fractions from acetone-hexane gives12a-fluoropregnane-l1,8-o1-3,20-dione (II) of the following properties:M.P. about 172; [a] +91 (c, 0.54 in chloroform);

Analysis.Calcd. for C H O F (350.42): C, 71.98; H, 8.90. Found: C,71.50; H, 9.19.

If 11p,1ZB-epoxypregnane-Zl-ol-3,20-dione ZI-acetate,11,8,12,8-epoxy-M-pregnene-3,20-dione, or 11B,12,8-epoxy- A-pregnene-21-ol-3,2O-dione 21-acetate is substituted for11,9,12/3-epoxypregnane-3,20-dione in the procedure of Example 1 or 2,the corresponding 12a-chloro-l1/3-h droxy and IZa-flllOlO-ll/S-hYdIOXYsteroid derivatives are prepared, respectively.

EXAMPLE 3 4/3-br0m0-12aa-chl0r0pregnane-11,8-0l-3,20-di0ne (III) To asolution of 5 0 mg. of 12u-chloropregnane-1l fl-ol- 3,20-dione in 10 m1.of glacial acetic acid is added a drop of 10% hydrogen bromide in aceticacid and then dropwise a solution of 25 mg. of bromine in 1 ml. ofglacial acetic acid. After addition of 30 mg. of solid sodium acetate,the solvent is removed in vacuo and the residue taken up in chloroform.The resulting chloroform solution is washed with dilute sodiumbicarbonate and water and after drying over sodium sulfate evaporated todryness. The crystalline residue (about 75 mg.) consists of essentiallypure lZea-chloro-4 8-bromopregnane-l13-01-330- dione, M.P. about 184-186(dec.); [m] |-10O (c, 0.5 in chloroform);

x232 2.95 (OH) 5.78;; (4-bromo-3-ketone), 5.92; (ZO-keto).

EXAMPLE 4 4B-br0m0-12a-fluoropregnane-11/8-0l-3,20-di0ne (IV) Followingthe procedure of Example 3 but substituting 50 mg. of12a-fiuoropregnane-11;3-ol-3,20-dione for the l2a-chloro reactant, about70 mg. of 4fi-bromo-l2a-fiuoropregnane-llfl-o1-3,20-dione are obtained.

Similarly, IZa-chloropregnane-l1B,21-dio1-3,20 dione 2l-acetate and12a-fluoropregnane-llfi,2l-diol-3,20-dione Z-acetate can be converted to4B-bromo-12a-chloropregnane-l113,21-diol-3,20-dione 21-acetate and4B-bromo-12afluoropregnane-l1B,21-diol-3,20-dione 21-acetate,respectively.

EXAMPLE 5 12a-chloro-M-pregnene-I1B-0l-3,20-dione [1 Zea-chloro- 1IB-hydroxyprogesterone] (V) A solution of 73 mg. of12a-chloro-4fl-bromo-pregnane- 11B-ol-3,20-dione and 135 mg. ofanhydrous lithium chloride in 5 ml. of redistilled dimethylformamide isheated at 100 under nitrogen for 2 and one-half hours. The solution isthen diluted with chloroform and extracted with water, dilute sodiumbicarbonate solution and again with Water. After drying over sodiumsulfate the solvent is evaporated in vacuo leaving a crystalline residue(about 47 mg.) of essentially pure l2a-chloro-A -pregnene-l1 3-01-3,20-dione. The latter is obtained in pure form after recrystallizationfrom acetone-hexane and has the following properties: M.P. about233-234; [a] |162 (c, 0.60 in chloroform);

N33; 239 111;]. (e=17,000) my 2.98;; (OH), 5.97;; (20-keto), 6.17 (A-3-ketone) 12a chloro-M-pregnene-lIdol-3,20 dione possesses aboutone-half the activity of cortisone acetate in the rat liver glycogenassay.

EXAMPLE 6 12a-flu0ro-A -pregnene-1 1;3-0l-3,20-di0ne [1 2a-fluoro-1 1/3-hydroxyprogesterone] VI) Following the procedure of Example 5 butsubstituting 72 mg. of l2a-fiuoro-4fi-bromopregnane-11[3-ol-3,20-dionefor the 12a-chloro-4,B-bromopregnane-l1B-ol-3,20-dione, there isobtained about 45 mg. of 12a-fluoro-A -pregnenel 1fl-ol-3,20-dione.

12a-fluoro-A -pregnene-11/3-ol-3,2O-dione possesses activity equal tohydrocortisone in the liver glycogen assay.

Similarly, 4B-bromo-l2a-chloropreguane 115,21-diol- 3,20-dione21-acetate and 4fl-bromo-l2a-fiuoropregnane- 1lB,2l-diol-3,20-dione2l-acetate can be converted to 12mchlorocorticosterone 21-acetate and12ot-fluorocorticosterone 21-acetate, respectively.

EXAMPLE 7 1 2a-chl0r0-A -pregnene-3 ,1 1 ,20-tri0ne [1 Za-ch loro- 1 1-ket0pr0gesterone] (VII) To a solution of 10 mg. of 12a-chloro-A-pregnene- 1lp-ol-3,20-dione in 1 ml. of glacial acetic acid is added asolution of 3.5 mg. of chromium trioxide in 1 ml. of glacial aceticacid. Ten minutes later the chromium trioxide is destroyed by theaddition of one-fourth ml.

of ethanol and the solution concentrated to a syrup in vacuo. Theresidue is taken up in chloroform and extracted with water, dilutesodium bicarbonate and again with water. After drying over sodiumsulfate, the chloroform is evaporated in vacuo and the semi-crystallineresidue chromatographed on 200 mg. of sulfuric acidwashed alumina.Elution of the column with a mixture containing 25% benzene and hexanefurnishes crystalline material which on recrystallization from ethanolmelts at about 152-154; [m] (c, 1.00 in chloroform);

A313; 237 mp, (e=15,l00) A23?! 5.83-5.87p, 5.97;L, 616p. 12a-ehloro-A-pregnene-3,11,20-trione possesses about one-half of the activity ofcortisone acetate in the rat liver glycogen assay.

EXAMPLE 8 Following the procedure of Example 7 but substituting 10 mg.of l2ea-fluoroA -pregnene-1lfl-ol-3,20-dione for the 12a-chlororeactant, there is obtained 12a-fluoro-A pregnene-3,l 1,20-trione.

In a similar manner, 12ot-chlorocorticosterone 21-acetate and12a-fluorocorticosterone 21-acetate are oxidized to12a-chloro-ll-dehydrocorticosterone acetate and 120sfluoro-ll-dehydrocorticosterone acetate, respectively.

The invention may be otherwise embodied within the scope of the appendedclaims.

What is claimed is:

1. 4 8 bromo 12oz halopregnane llfi o1 3,20- dione, wherein the halogenhas an atomic weight greater than 18 and less than 36.

2. 4/3 bromo 12a chloropregnane llfl o1 3,20- dione.

3. A steroid of the general formula CHzY wherein X is selected from thegroup consisting of chloro and fluoro, Y is selected from the groupconsisting of hydrogen, hydroxy and the acyloxy radical of a hydrocarboncarboxylic acid of less than ten carbon atoms, and Z is selected fromthe group consisting of hydrogen and Ot-hydTOXy.

References Cited in the file of this patent UNITED STATES PATENTS OTHERREFERENCES Shoppee: Chemistry of the Steroids (London: ButterworthsScientific Publications, 1958), pages and 186.

3. A STEROID OF THE GENERAL FORMULA